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Synthesis and in vitro cytotoxic activity of N-, F-, and S-ether derivatives of podophyllotoxin fatty acid adducts

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Lipids

Abstract

This paper represents the first synthesis, spectroscopic characterization, and antitumor evaluation of F-, N-, and S-containing C4α-FA derivatives of podophyllotoxin. In a synthetic strategy, a FA unit of 4-O-podophyllotoxinyl 12-hydroxyoctadec-Z-9-enoate 2, a derivative of podophyllotoxin, was functionalized at the C−12 position by incorporating the F atom and N-containing moieties. The FA olefin (Z, C−9/C−10) of 2 was hydrogenated to produce a derivative possessing a hydroxy function (C−12) on a saturated C18 FA chain. In another synthetic strategy, two S-ethers of podophyllotoxin (C4α) were synthesized from a terminal unsaturated FA analog, 4-O-podophyllotoxinyl undec-10-enoate. Syntheses were achieved through effective synthetic procedures; 1H NMR, 13C NMR, IR, and high-resolution mass data proved excellent tools to characterize these derivatives. In vitro antitumor activity was investigated against a panel of five human neoplastic cell lines, SK-MEL (malignant, melanoma), KB (epidermal carcinoma, oral), BT-549 (ductal carcinoma, breast), SK-OV-3 (ovary carcinoma), and HL-60 (human leukemia). Keeping in view the severe lack of tumor selectivity of podophyllotoxin over normal cells, we assayed new analogs against noncancerous mammalian VERO (African green monkey kidney fibroblast) cell lines to gauge their extent of toxicity. Several of these compounds showed excellent moderation of antitumor activity. In general, we found excellent growth inhibition against the human leukemia cell line (HL-60), particularly for the analogs containing S-ethers and carbamates. None of the compounds were toxic to normal cell lines.

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Abbreviations

DAST:

diethylaminosulfur trifluoride

DCC:

dicyclohexylcar-bodiimide

DMAP:

dimethyl aminopyridine

NCI:

National Cancer Institute

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Authors and Affiliations

  1. National Center for Natural Product Research, Research Institute of Pharmaceutical Sciences, University of Mississippi, 38677, University, Mississippi

    Jamal Mustafa, Shabana I. Khan, Guoyi Ma, Larry A. Walker & Ikhlas A. Khan

  2. Department of Pharmacology, University of Mississippi, 38677, University, Mississippi

    Larry A. Walker & Ikhlas A. Khan

  3. Department of Pharmacognocy, School of Pharmacy, University of Mississippi, 38677, University, Mississippi

    Jamal Mustafa, Shabana I. Khan, Guoyi Ma, Larry A. Walker & Ikhlas A. Khan

Authors
  1. Jamal Mustafa
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  2. Shabana I. Khan
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  3. Guoyi Ma
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  4. Larry A. Walker
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  5. Ikhlas A. Khan
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Correspondence to Ikhlas A. Khan.

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Mustafa, J., Khan, S.I., Ma, G. et al. Synthesis and in vitro cytotoxic activity of N-, F-, and S-ether derivatives of podophyllotoxin fatty acid adducts. Lipids 40, 375–382 (2005). https://doi.org/10.1007/s11745-006-1397-x

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  • DOI: https://doi.org/10.1007/s11745-006-1397-x

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